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WO2023031960A1 - Nouveau polymorphe cristallin de lurbinectédine et méthode améliorée pour la préparation de lurbinectédine - Google Patents

Nouveau polymorphe cristallin de lurbinectédine et méthode améliorée pour la préparation de lurbinectédine Download PDF

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Publication number
WO2023031960A1
WO2023031960A1 PCT/IN2022/050772 IN2022050772W WO2023031960A1 WO 2023031960 A1 WO2023031960 A1 WO 2023031960A1 IN 2022050772 W IN2022050772 W IN 2022050772W WO 2023031960 A1 WO2023031960 A1 WO 2023031960A1
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WIPO (PCT)
Prior art keywords
lurbinectedin
crystalline polymorph
preparation
compound
organic solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
PCT/IN2022/050772
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English (en)
Inventor
Srinivasa Chary CHINTALAPATI
Thirupathi Kotte
Srinivasan ABAYEE KALIYAPERUMAL
Shankar Reddy BUDIDETI
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Natco Pharma Ltd
Original Assignee
Natco Pharma Ltd
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Filing date
Publication date
Application filed by Natco Pharma Ltd filed Critical Natco Pharma Ltd
Priority to US18/686,936 priority Critical patent/US20240352039A1/en
Priority to CA3229559A priority patent/CA3229559A1/fr
Publication of WO2023031960A1 publication Critical patent/WO2023031960A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems

Definitions

  • the present invention relates to novel stable crystalline polymorph, Form- N of Lurbinectedin.
  • the present invention also relates to an improved and industrially viable process for the preparation of Ecteinascidin derivative i.e., Lurbinectedin.
  • Background of the invention Lurbinectedin is an Ecteinascidin Derivative.
  • Lurbinectedin is chemically known as (1’R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy-6’,9-dimethoxy-4,10,23- trimethyl-19-oxo-2’,3’,4’,6,7,9’,12,13,14,16-decahydro-6aH-spiro[7,13-azano- 6,16-(epithiopropanooxymethano)[1,3]dioxolo[7,8]isoquinolino[3,2-b][3] benzazocine-20,1’-pyrido[3,4-b]indol]-5-yl acetate and having the structure below Lurbinectedin Lurbinectedin is approved under the brand name “ZEPZELCA” and it is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.
  • SCLC metastatic small cell lung cancer
  • the U.S. patent No. 7763615 discloses synthesis and characterization of Lurbinectedin.
  • Angew Chem Int Ed Engl. 2019 Mar 18;58(12):3972-3975 has reported process for the preparation of Trabectedin and Lurbinectedin, wherein compound III was prepared from compound–IV by using 4-formyl-1- methylpyridiniumbenzenesulfonate, the reaction is not meeting large-scale requirement as it is giving low yield as well as inconsistent for completion of reaction. It also observed that the quality of 4-formyl-1-methylpyridinium benzenesulfonate is very important for the reaction success. Commercial availability of ultra-quality of 4-formyl-1-methylpyridiniumbenzenesulfonate is always risk.
  • the patent application WO2021/099635 A1 described about amorphous form-A and Form-B. Compared to Form-A, Form-B is shown advantages of physical properties as per this patent application.
  • the inventors of the present invention have developed an alternative improved process for the preparation of Lurbinectedin. The present process is simple, cost effective and feasible in large scale production. The inventors of the present invention also have developed novel and stable polymorph for Lurbinectedin and commercially viable process for the preparation of Lurbinectedin.
  • Object of the Invention One object of the present invention is to provide a process for the preparation of Lurbinectedin, which is simple, economical, and suitable for industrial scale up. Another objective of the present invention is to provide a novel and stable crystalline form- N of Lurbinectedin.
  • Main aspect of the present invention relates to crystalline polymorph, Form- N of Lurbinectedin.
  • Another aspect of the present invention relates to crystalline polymorph, Form-N of Lurbinectedin characterized by its powder X-ray diffraction (PXRD) Pattern having peaks at about 4.8 ⁇ 0.2, 9.0 ⁇ 0.2, 9.5 ⁇ 0.2 and 11.8 ⁇ 0.22 ⁇ .
  • PXRD powder X-ray diffraction
  • Yet another aspect of the present invention is related to process for the preparation of crystalline polymorph, Form-N of Lurbinectedin comprising the steps of: a) dissolving Lurbinectedin in organic solvent or mixture thereof, b) distil or co distil the organic solvent with or without vacuum to obtain suspension, c) cool the suspension, filter and wash with organic solvent or mixture thereof to obtain crystalline polymorph, Form-N of Lurbinectedin.
  • Fig. 1 XRPD diffractogram of novel crystalline polymorph, Form-N of Lurbinectedin.
  • Fig.2 DSC thermogram of novel crystalline polymorph, Form-N of Lurbinectedin.
  • Fig.3 Infrared spectrum of novel crystalline polymorph, Form-N of Lurbinectedin.
  • Fig. 4 Thermogravimetric analysis of novel crystalline polymorph, Form-N of Lurbinectedin.
  • Main embodiment of the present invention relates to crystalline polymorph, Form-N of Lurbinectedin.
  • Another embodiment of the present invention relates to crystalline polymorph, Form-N of Lurbinectedin characterized by its powder X-ray diffraction (PXRD) Pattern having peaks at about 4.8 ⁇ 0.2, 9.0 ⁇ 0.2, 9.5 ⁇ 0.2 and 11.8 ⁇ 0.22 ⁇ .
  • PXRD powder X-ray diffraction
  • Yet another embodiment of the present invention related to process for the preparation of crystalline polymorph, Form-N of Lurbinectedin comprising the steps of: a) dissolving Lurbinectedin in organic solvent or mixture thereof, b) distil or co distil the organic solvent with or without vacuum to obtain suspension, c) cool the suspension, filter and wash with organic solvent or mixture thereof to obtain crystalline polymorph, Form-N of Lurbinectedin.
  • the present invention relates to crystalline polymorph, Form-N of Lurbinectedin that exhibits an PXRD pattern as shown in Figure-1.
  • Form-N of Lurbinectedin can be characterized by DSC as shown in Fighure-2.
  • Form-N of Lurbinectedin is anhydrous in nature.
  • Form-N of Lurbinectedin has a water content less than 1% w/w.
  • organic solvent preferably acetonitrile and a freshly prepared buffer solution by using NaOAc and AcOH.
  • anhydrous zinc sulfate and metal glyoxylate or mixture of glyoxylate or thereof preferably Magnesium glyoxylate.
  • the reaction mass was stirred 25-30°C, the reaction completion was monitored and diluted with organic solvent preferably Dichloromethane; organic layer was washed with water. The organic layer was concentrated, and the crude compound was isolated by from hexane and in-situ intermediate Compound-III was prepared.
  • Obtained compound exhibits with novel crystalline polymorph, Form-N of Lurbinectedin with more than 99 % purity by HPLC.
  • the novel crystalline polymorph, Form-N of Lurbinectedin is used in pharmaceutical composition preparation such as solutions, lyophilized compositions, etc., with suitable excipients for intravenous administration.
  • Inventors of the present application have come across a novel crystalline form of Lurbinectedin. Which is consistently reproducible, does not have the tendency to convert to other forms, and found to be more stable.
  • Advantages of the present invention 1.
  • the process of the present invention is feasible to produce on commercial scale of Lurbinectedin without any apprehension.
  • Novel crystalline polymorph, Form-N of Lurbinectedin is stable. 3.
  • Novel crystalline polymorph, Form-N is stable at ambient temperature and at elevated temperatures. 4.
  • the novel crystalline polymorph, Form-N of Lurbinectedin is substantially anhydrous and is stable at ambient storage conditions.
  • PXRD Method of Analysis PXRD analysis of the crystalline form -N Lurbinectedin were carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.
  • DSC Method of Analysis Differential scanning calorimetric (DSC) analysis was performed with TA/2500 Discovery. Samples of about 2 to 3 milligrams held in a Tzero Aluminum Hermetic closed pan were analyzed at a heating rate of 10° C. per minute.
  • Example 1 Process for the preparation of Compound-III Compound-IV (6.5g) is dissolved in acetonitrile at 25-30°C, treated with magnesium glyoxylate (10.6g) in the presence of sodium acetate buffer solution & zinc sulphate. After completion of the reaction, it is quenched into a mixture of dichloromethane-DM water. Separated the layers, the aqueous layer is extracted with dichloromethane.
  • Example 2 Process for the preparation of Compound-II Compound-III (5.8 g) is reacted with 5-methoxytryptamine (2.2 g) in presence of acetic acid (0.84g,) at 25-30°C in distilled toluene. The reaction mass is initially stirred at 25-30°C for about 5h and followed by at 40-45°C for about 16h. The reaction is monitored by HPLC. Upon completion of the reaction, insoluble mass is filtered.
  • Example 3 Process for the preparation of novel crystalline polymorph, Form- N of Lurbinectedin.
  • Compound-II (4.2g) is reacted with silver nitrate (13.48 g) in presence of aq. acetonitrile at 20-23°C and the reaction is monitored by HPLC analysis.
  • reaction mass is quenched into the mixture of dichloromethane-15% aq. sodium chloride solution-8% aq. sodium bicarbonate solution at 5-10°C and insoluble mass are filtered through hyflo.
  • the organic layer is separated, and aq. layer back extracted with dichloromethane.
  • the combined organic layer is washed with DM water, dried over anhydrous sodium sulphate, and filtered.
  • the filtrate is concentrated on rota vapor under a vacuum at below 25°C to yield crude Lurbinectedin compound.
  • the crude product is purified by flash chromatography and pure fractions are extracted with dichloromethane.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne une nouvelle forme-N polymorphe cristalline de lurbinectédine et une méthode de préparation de lurbinectédine.
PCT/IN2022/050772 2021-08-31 2022-08-30 Nouveau polymorphe cristallin de lurbinectédine et méthode améliorée pour la préparation de lurbinectédine Ceased WO2023031960A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US18/686,936 US20240352039A1 (en) 2021-08-31 2022-08-30 Novel crystalline polymorph of lurbinectedin and improved process for the preparation of lurbinectedin
CA3229559A CA3229559A1 (fr) 2021-08-31 2022-08-30 Nouveau polymorphe cristallin de lurbinectedine et methode amelioree pour la preparation de lurbinectedine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202141039393A IN202141039393A (fr) 2021-08-31 2021-08-31
IN202141039393 2021-08-31

Publications (1)

Publication Number Publication Date
WO2023031960A1 true WO2023031960A1 (fr) 2023-03-09

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PCT/IN2022/050772 Ceased WO2023031960A1 (fr) 2021-08-31 2022-08-30 Nouveau polymorphe cristallin de lurbinectédine et méthode améliorée pour la préparation de lurbinectédine

Country Status (4)

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US (1) US20240352039A1 (fr)
CA (1) CA3229559A1 (fr)
IN (1) IN202141039393A (fr)
WO (1) WO2023031960A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025059336A1 (fr) * 2023-09-13 2025-03-20 Navinta, Llc Procédé amélioré pour préparer de la lurbinectédine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003014127A1 (fr) * 2001-08-07 2003-02-20 Pharma Mar, S.A. Analogues antitumoraux
WO2021099635A1 (fr) * 2019-11-21 2021-05-27 Pharma Mar, S.A. Nouvelle forme à l'état solide de lurbinectédine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003014127A1 (fr) * 2001-08-07 2003-02-20 Pharma Mar, S.A. Analogues antitumoraux
WO2021099635A1 (fr) * 2019-11-21 2021-05-27 Pharma Mar, S.A. Nouvelle forme à l'état solide de lurbinectédine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VIPPAGUNTA S R, BRITTAIN H G, GRANT D J W: "Crystalline solids", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER, AMSTERDAM , NL, vol. 48, no. 1, 16 May 2001 (2001-05-16), Amsterdam , NL , pages 3 - 26, XP008121199, ISSN: 0169-409X, DOI: 10.1016/S0169-409X(01)00097-7 *

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IN202141039393A (fr) 2023-03-03
CA3229559A1 (fr) 2023-03-09

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